During the past seven years of this SPORE project, we were first to identify in pancreatic cancer the nearly ubiquitous inactivation of the pl6 gene, and the genetic inactivation of BRCA2, TGF-beta receptors I and II, activin receptor IB, LKB1/STK11 (Peutz-Jeghers), DPC4/SMAD4, mitochondrial genome, DCC, and mismatch repair genes including MLH1. We confirmed the mutations of MKK4 and identified a distinctive nature of K-ras wildtype tumors. The discoveries provided insights into tumor biology, familial aggregation, and histologic tumor classification now applied in clinical practice. Our long-term goal is to identify the metabolic and regulatory pathways that are altered reproducibly in pancreatic tumorigenesis in order to construct a general theory that explains tumor behavior, provides improved epidemiologic and diagnostic tools, and enables rational therapy. In the proposed grant period, we will acquire essential knowledge to advance this goal: 1) Identify novel genetic alterations in pancreatic cancer. We will apply techniques that have proven efficient in this effort, including the evaluation of sites of homozygous deletion and the consideration of candidate genes based on pathway relationships. 2) Extend the genetic discoveries made in pancreatic and other tumor systems. We will map the homozygome of pancreatic cancer; the genes contained within homozygous deletions are likely to include not only the mundane "passenger genes", but also additional suppressor genes and biochemical defects that could suggest attractive therapeutic targets. Genes known to be altered in other tumor types will be examined in pancreatic cancer as an essential component in construction of a genetic basis for the disease. 3) Determine the clinical relevance of the genetic alterations identified. This has proven to be a highly successful application of this project. We will evaluate associations among known genetic alterations and a set of demographic, clinical, and histologic characteristics. This will be invaluable as a basis for clinical practice.